tbuckley/cabot-search huggingface dataset:
Abstract P5-02-10: In-silico approaches that detect immune contexture to trastuzumab response in neo-adjuvant studies
Authors: Dalal AlSultan, Alex J. Eustace, Stephen F. Madden, John Crown
Journal: Cancer Research (2023)

Abstract Introduction: Computational approaches have aided in estimating cellular composition of the tumour microenvironment. The evaluation of immune composition in tumours before treatment may predict pathologic complete response (pCR). The aim of the study was to perform a meta-analysis of HER2-positive breast cancer subjects who received neoadjuvant trastuzumab to detect associations between immune cells measured by CIBERSORT and ESTIMATE and pCR. Methods: PubMed was used to identify transcriptomic data of HER2-positive breast cancer patients who received neoadjuvant trastuzumab. Baseline data from eight neoadjuvant studies (N=338) was downloaded from GEO. Data from each study was background corrected and quantile normalised using ‘limma’ or ‘oligo’ packages in R. Immune profiles per sample was generated using computational softwares CIBERSORT and ESTIMATE, and were then linked to pCR status. Correlations between immune contexture and pCR for each study were interpreted using statistical testing. Meta-analysis by a logistic regression model was conducted on studies which passed assumptions to identify CIBERSORT immune subsets robust to pCR. Results: CIBERSORT results showed that three studies had reduced T follicular helper cells (Tfh) (Brodsky p=0.38, CHER-LOB p=0.17, TransNOAH p=0.25) and two studies had reduced plasma cells (CHER-LOB p=0.15, Brodsky p=0.38) in the pCR group, but was not significant after multiple correction. ESTIMATE analysis showed that data from two studies had elevated immune infiltration in pCR (Brodsky p=0.19, CHER-LOB p=0.10) but was not significant. A meta-analysis of pooled data from four studies (TRIO-US B07, 03-311, TransNOAH, CHER-LOB) showed that low Tfh (p=0.053, OR=0.04, CI [0.0012-0.99]) and high memory B-cells (p=0.008, OR=2126.9, CI [8.12-7.65 × 10+5]) prior to trastuzumab treatment may be associated with a better chance of achieving pCR. Conclusion: Results from our meta-analysis proposed that memory B- and T follicular helper subsets may predict a role in achieving pCR. Incorporating studies with larger sample cohorts such as the CALGB-40601 (N=265) study can achieve statistical power of this analysis. Citation Format: Dalal AlSultan, Alex J. Eustace, Stephen F. Madden, John Crown. In-silico approaches that detect immune contexture to trastuzumab response in neo-adjuvant studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-10.
Abstract P6-11-13: Ferroptosis Heterogeneity in Triple-Negative Breast Cancer Reveals an Innovative Immunotherapy Combination Strategy
Authors: Fan Yang, Yi Xiao, Jia-Han Ding, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: Cancer Research (2023)

Abstract Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n=465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors. Citation Format: Fan Yang, Yi Xiao, Jia-Han Ding, Yi-Zhou Jiang, Zhi-Ming Shao. Ferroptosis Heterogeneity in Triple-Negative Breast Cancer Reveals an Innovative Immunotherapy Combination Strategy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-13.
Abstract P2-26-15: CCR7 expression in Inflammatory breast cancer
Authors: Wintana Balema, Savitri Krishnamurthy, Alison Lawrence, Megan Rodriguez, Richard Larson, Natalie Fowlkes, Naoto T. Ueno, Wendy Woodward
Journal: Cancer Research (2023)

Abstract Background: Inflammatory breast cancer is an aggressive breast cancer characterized by florid congestion of lymphovascular spaces by tumor emboli. CCR7 is an immune cell receptor that mediates traffic of immune cells into lymphatics that can be expressed on tumor cells. An RNA-seq screen of tumor promoting mammary glands in mice identified CCR7 as an upregulated signal in mammary glands that promoted IBC-like skin invasion. We examined the expression of CCR7 in IBC cell lines and patients to determine the prevalence of this receptor in IBC. Methods: Protein lysates from IBC and non-IBC cell lines were subjected to immunoblotting using anti CCR7 (R&amp;D systems). An IBC tissue microarray from post-chemotherapy mastectomy specimens of 39 patients, each with three replicates was subjected to immunohistochemical staining for CCR7 (Invitrogen, catalog number MA5-31992) performed using a Leica Bond RX autostainer with an incubation time of 60 minutes at 1:15,000 after 20 minutes of heat-induced antigen retrieval at pH 6.0. In 15 cases there were no tumor cells observed in the cores. Staining was scored by an expert breast pathologist for intensity and percent tumor stained. Staining patterns were scored. Descriptive statistics were examined for representation by receptor subtype. Results: CCR7 staining was strong in all lines examined including MCF7, SUM149, SUM190, MDA-IBC, and SUM159. Among 24 IBC patient cores with tumor in the tissue, 23 (96%) expressed CCR7 in tumor, 15 with complete membranous staining and 9 with incomplete membranous staining. In one case with LVSI the emboli were CCR7 positive. Among the 24 positive cases, 22 were 3+ intensity while two were 2+. Nine CCR7+ cases were estrogen receptor (ER) ER+, 8 ER-, and 6 unknown. HER2 status is pending. Conclusions: CCR7 expression is present across tumor subtypes in IBC cell lines and in both ER+ and ER- patient tumors. Given developing novel pharmacologic targeting of CCR7, this target warrants further investigation in IBC and other breast cancers. Citation Format: Wintana Balema, Savitri Krishnamurthy, Alison Lawrence, Megan Rodriguez, Richard Larson, Natalie Fowlkes, Naoto T. Ueno, Wendy Woodward. CCR7 expression in Inflammatory breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-15.
Abstract P4-03-39: Breast density and Body Mass Index association with breast cancer molecular subtypes in early breast cancer Spanish population
Authors: Isabel Calvo, Marta González, Fernando Neria, Isabel Gallegos, Lourdes García-Sánchez, Silvia Pérez, Laura G. Estévez
Journal: Cancer Research (2023)

Abstract Obesity is a major health problem and is closely related to the incidence and progression of breast cancer (BC). Likewise, mammogram breast density (MBD) is a risk factor for breast cancer. This study aims to analyze the potential association between BMI (Body Mass Index) and MBD with different molecular subtypes of BC. The interaction with cholesterol, vitamin D, insulin levels, and lifestyle, will also be evaluated. Materials and methods: This is a transversal, descriptive, multicenter study involving women with a recent diagnosis of early BC for one-year duration (November 2019 to October 2020). BMI was classified as obesity (BMI &amp;gt;=30 kg/m2), overweight (&amp;gt;=25 kg/m2), and normal weight (18-25 Kg/m2). American college of radiology was used to classify MBD into 4 categories: A, B, C, and D. Data of weight, height, MBD, molecular subtype (according to 13th St Gallen International Breast Cancer Panel), cholesterol, insulin, vitamin-D, hypertension, diabetes, exercise, and lifestyle were collected at the moment of diagnosis. Results: 162 women with a recent diagnosis of early BC have been successively evaluated in 3 Spanish hospitals. The median age was 52 years, and 49.1% were postmenopausal. Molecular subtypes were: 43% luminal-A, 25% luminal-B, 17% HER2+, and 15% triple-negative. 7% of patients were MBD type A, 17% type B, 55% type C, and 21% type D. 52% were normal weight, 32% overweight, and 16% obese. 48% of women had normal cholesterol levels and 60% normal vitamin D. There was not association between BMI and molecular subtype, however considering menopausal status, BMI was significantly higher in postmenopausal patients with Luminal A subtype (p= 0.011) and HER2+ subtype (p= 0.027). There was no association between MBD and molecular subtype. However, there were significant differences between BMI and MBD (p&amp;lt; 0.001) with lower BMI in patients who had MBD type C or D. Patients with higher BMI had lower HDL-Cholesterol (p&amp;lt; 0.001) and higher levels of insulin (p&amp;lt; 0.001). Conclusion: This study showed a higher BMI in Luminal A and HER2 positive postmenopausal BC patients. Higher BMI was shown in patients with low MBD independently of menopausal status. More studies are needed to understand the role of obesity and molecular subtype of breast cancer. Citation Format: Isabel Calvo, Marta González, Fernando Neria, Isabel Gallegos, Lourdes García-Sánchez, Silvia Pérez, Laura G. Estévez. Breast density and Body Mass Index association with breast cancer molecular subtypes in early breast cancer Spanish population. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-39.
Abstract P6-12-02: Connecting Fluctuations in Estrogen Production, Release, and Action with Hormone-Dependent Gene Expression in Breast Cancers
Authors: Hyung Bum Kim, William L. Kraus
Journal: Cancer Research (2023)

Abstract Estrogens are steroid hormones that play a key role in a wide range of physiological and pathological processes. Estrogen receptor-alpha, ERɑ, functions primarily as a nuclear transcription factor (TF) through ligand-dependent activation by 17β-estradiol (E2), the predominant naturally-occurring estrogen. This results in dimerization, DNA binding to cis-regulatory elements called enhancers, and gene regulatory function of ERɑ. In vivo, E2 production and action fluctuates during reproductive cycles and possibly even in a circadian manner. In tissues and cells, E2-regulated gene expression is dynamic, with rapid induction of enhancer formation and target gene expression (or repression), followed by enhancer “decommissioning” and cessation of the gene regulatory effects. The effects of sustained E2 production and signaling, fluctuations in E2 levels, and removal of E2 on estrogen-regulated gene expression are unknown. Classical experiments exploring the gene regulatory effects of E2 involve stimulation of cultured cells throughout the duration of the experiment with a continuous and typically high dose of hormone, with the cells harvested at the end of the stimulation period. While this has allowed us to understand the molecular underpinnings of signal-dependent transcription, it has not allowed analysis of physiological fluctuations in estrogen signaling involving periods of stimulation (i.e., the presence of hormone) and non-stimulation (i.e., the absence of hormone). In our studies, we are applying a combination of next generation sequencing techniques and fluorescence microscopy to investigate signal-dependent responses to fluctuating and short duration E2 exposures using ERɑ-positive MCF-7 human breast cancer cells after E2 treatment and removal. Our initial results suggest that different E2 target genes respond differently to low dose E2 treatment and E2 withdrawal. Moreover, for some E2 target genes, sustained E2 treatment may not be required for a complete E2 transcriptional response. With these studies, we hope to connect physiological aspects of E2 production, release, and action with the molecular mechanisms of E2-dependent gene expression - an aspect of our understanding of estrogen signaling that has been lacking. Citation Format: Hyung Bum Kim, William L. Kraus. Connecting Fluctuations in Estrogen Production, Release, and Action with Hormone-Dependent Gene Expression in Breast Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-12-02.
Abstract P6-12-03: Proinflammatory and estrogen signaling modulates the chemoresistance and metastasis of breast cancer cells through post-translational modifications of pioneering factor FOXA1
Authors: Shen Li, Hector L. Franco, Hyunsoo Kim, Rosemary N. Plagens, Raul Mendez-Giraldez, Colby Tubbs, Venkat Malladi, Joseph Garay
Journal: Cancer Research (2023)

Abstract ER-positive breast cancers compose most breast cancers at the time of diagnosis and are primarily driven by mitogenic estrogen signaling. In ER-positive breast cancers, the pioneer transcription factor FOXA1 plays a critical role in the estrogen receptor (ER) function. It binds to condensed chromatin and promotes chromatin accessibility for subsequent ER binding upon estrogen stimulation. We have reported that TNFa-stimulated proinflammatory signaling relocates FOXA1 to a new set of latent enhancers, which initiates the binding of estrogen liganded ER and subsequent expression of a unique transcriptome with clinical significance. The redistribution of FOXA1 occurs within 40 mins of the TNFa treatment, which implies a rapid signaling cascade that arises from changes to either FOXA1’s post-translational modifications (PTMs) or its binding partners. To understand this genomic redistribution of FOXA1, we compared the post-translational modifications (PTMs) of FOXA1 from Vehicle, E2, TNFa, and E2+TNFa treated MCF-7 breast cancer cells. More than five acetylation and phosphorylation events have been identified around the DNA binding domain of FOXA1 by semi-quantitative and quantitative mass spectrometry approaches, and their abundance varies across treatments. To study these PTMs of FOXA1, we used CRISPR/Cas9 to create specific knock-in mutations to mimic or prevent acetylation events in MCF-7 cells. Specifically, we engineered MCF-7 cell lines where K270 was mutated to glutamine (K270Q) to mimic acetylation. And for comparison, we also created cell lines where K270 was mutated to arginine (K270R) to prevent acetylation of FOXA1. Our data, including FOXA1 ChIP-seq and RNA-seq, revealed the genomic redistribution of FOXA1 with these PTMs, which subsequently alters gene expression programs and promotes cell growth, migration, or chemoresistance. These results were confirmed in other ER+ cell lines (such as T47D cells) providing evidence for the generalizability of our findings. Taken together, our data suggest that inflammatory signaling signaling can reshape the enhancer landscape of FOXA1 through post-translational modifications, resulting in changes to estrogen signaling that have profound effects on breast cancer biology. Citation Format: Shen Li, Hector L. Franco, Hyunsoo Kim, Rosemary N. Plagens, Raul Mendez-Giraldez, Colby Tubbs, Venkat Malladi, Joseph Garay. Proinflammatory and estrogen signaling modulates the chemoresistance and metastasis of breast cancer cells through post-translational modifications of pioneering factor FOXA1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-12-03.
Abstract PD6-03: PD6-03 Serum methylmalonic acid concentrations at breast cancer diagnosis strongly correlate with frailty: a retrospective cross-sectional study
Authors: Qi Wu, Sigrid Hatse, Cindy Kenis, Yentl Lambrechts, Kevin Punie, Patrick Neven, Ann Smeets, Annouschka Laenen, Ana Gomes, Sarah-Maria Fendt, Hans Wildiers
Journal: Cancer Research (2023)

Abstract Introduction: Frailty commonly occurs in older persons, including those with breast cancer diagnoses. Methylmalonic acid (MMA), a metabolite and by-product of propionate metabolism, is known to increase significantly with aging. The relation between MMA concentrations and frailty is currently unknown. Objectives: A cross-sectional study was performed to study the association between baseline serum MMA concentrations and clinical frailty (estimated by G8 screening) in older patients with newly diagnosed breast cancer. Methods: 163 patients ≥70 years old with early-stage breast cancer were included (median age 76y). G8 screening and serum sample collection were performed at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry (LC-MS-MS). Results: MMA concentrations significantly increased with age (rs=0.3, p&amp;lt;.0001) and serum creatinine levels (rs=0.5, p&amp;lt;.0001) in this older population. The group with an abnormal G8 (≤14/17 = ‘frail’, 48% of patients) had significantly higher MMA levels than the group with normal G8 (&amp;gt;14/17 = ‘fit’, 52%): 250nM vs. 189 nM, respectively (p=.0002). Higher MMA concentrations were independently associated with abnormal G8 (Odds ratio, 1.003, 95%CI 1.0 to 1.006, p=.04) after adjusting for age and serum creatinine levels. Among the different components of G8, MMA concentrations correlated most with weight loss (rs= -0.18, p=.02), mobility (rs= -0.23, p=.002), and polypharmacy (rs= -0.22, p=.005). Conclusion: Elevated serum MMA concentrations at breast cancer diagnosis are significantly associated, not only with age but also independently with clinical frailty in older patients with early-stage breast cancer. MMA may be further evaluated as a biomarker of frailty in older persons with breast cancer. Citation Format: Qi Wu, Sigrid Hatse, Cindy Kenis, Yentl Lambrechts, Kevin Punie, Patrick Neven, Ann Smeets, Annouschka Laenen, Ana Gomes, Sarah-Maria Fendt, Hans Wildiers. PD6-03 Serum methylmalonic acid concentrations at breast cancer diagnosis strongly correlate with frailty: a retrospective cross-sectional study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-03.
Abstract P6-09-05: Using Mixed Methods to Examine Clinician and Patient Use of Terminology to Describe Trastuzumab Biosimilars
Authors: Elizabeth Papautsky, Devika Salunke, Hannah Montague, Martha Carlson, Sheila Johnson, Deanna Attai, Maryam Lustberg
Journal: Cancer Research (2023)

Abstract Although the uptake of trastuzumab biosimilars to treat HER2-positive breast cancer is growing, knowledge gaps remain for both, patients and clinicians. In a mixed-methods study, inconsistencies in terminology used to describe trastuzumab biosimilars. We analyzed open-ended questions from surveys (n = 143 breast cancer patients, n = 33 medical oncologists) and interviews (n = 8 patients, n = 4 oncologist, nurse, pharmacists) indentifying terminology as an a priori (top-down) category for qualitative thematic analysis. We specifically looked for examples of inconsistent or incorrect use of terminology in the interviews. Findings suggest that 1) terminology used to refer to trastuzumab biosimilars is variable across patients and some is not representative of the formal definition (e.g. generic, generic-like, interchangeable, Herceptin, generic Herceptin (as per how their oncologist refers to biosimilars) and 2) clinicians discussed the challenges of talking about biosimilars in a manner that is both understandable to patients and accurate. Specifically, one pharmacist highlighted concerns around this complexity and suggested that it should be part of clinician education to use the correct terminology, rather than using the term generic. A medical oncologist said that “Explaining biosimilars to a patient can be challenging” as part of their survey response. Lack of consistent terminology for trastuzumab biosimilars is a potential barrier to effective patient-clinician communication on this topic and may perpetuate lack of comprehension on the part of patients. Further, the intentional use (to make information more digestible to patients) of incorrect terminology by clinicians has the potential to negatively impact the patient-clinician relationship in cases where patients identify conflicting information on their own. The adoption of terminology that is consistent across clinicians and patient-facing resources on the introduction and description of trastuzumab biosimilars, may serve to facilitate common grounding among all roles. Citation Format: Elizabeth Papautsky, Devika Salunke, Hannah Montague, Martha Carlson, Sheila Johnson, Deanna Attai, Maryam Lustberg. Using Mixed Methods to Examine Clinician and Patient Use of Terminology to Describe Trastuzumab Biosimilars [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-09-05.
Abstract ED2-1: Cancer risks in patients with moderate penetrance gene mutations
Authors: Payal Shah
Journal: Cancer Research (2023)

Abstract The genetic landscape of inherited breast cancer is broad, spanning from high and moderate penetrance pathogenic variants in breast cancer susceptibility genes, to polygenic risk associated with the cumulative impact of single nucleotide polymorphisms (SNPs). This educational session will review the landscape of inherited breast cancer. The discussion will then focus on breast cancer susceptibility genes associated with moderately elevated risks of breast cancer including PALB2, ATM, CHEK2 and others. Recent data informing quantitative and qualitative cancer risk estimates, management recommendations, therapeutic implications, and reproductive considerations will be reviewed. Emerging issues and treatment strategies under investigation will also be discussed. Citation Format: Payal Shah. Cancer risks in patients with moderate penetrance gene mutations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED2-1.
Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention versus usual care on cardiovascular disease (CRHCP): an open-label, blinded-endpoint, cluster-randomised trial
Authors: Jiang He, Nanxiang Ouyang, Xiaofan Guo, Guozhe Sun, Zhao Li, Jianjun Mu, Dao Wen Wang, Lixia Qiao, Liying Xing, Guocheng Ren, Chunxia Zhao, Ruihai Yang, Zuyi Yuan, Chang Wang, Chuning Shi, Songyue Liu, Wei Miao, Guangxiao Li, Chung-Shiuan Chen, Yingxian Sun, Xingang Zhang, Jun Wang, Ying Zhou, Ning Ye, Zihan Chen, Pengyu Zhang, Zihao Fan, Nan Ye, Linlin Zhang, Danxi Geng, Shu Zhang, Qiyu Li, Qiying Qin, Canru Liu, Xiaoyu Zheng, Tao Wang, Li Jing, Boqiang Zhang, Qun Sun, Yu Yan, Yueyuan Liao, Qiong Ma, Chao Chu, Yue Sun, Dan Wang, Ling Zhou, Heng Ye, Haoran Wei, Hao Liu, Zhaoqing Sun, Liqiang Zheng, Yanli Chen, Ye Chang, Mohan Jiang, Hongmei Yang, Shasha Yu, Wenna Li, Ning Wang, Chunwei Wu, Lufan Sun, Zhi Du, Yan Li, Nan Gao, Xinchi Liu, Ying Wang, Mingang Huang, Yufang Zhou, Lingrui Meng, Jiawen Zhang, Zhen Huang, Huihui Chen, Yuxian Huang, Lingmin Sun, Xin Zhong, Hanmin Wang, Xinyan Hou, Huan Han, Baohui Jin, Hua He
Journal: The Lancet (2023)